Jonas Wessén
Amyloid Nucleation in Presence of Crowders
Master Thesis in Theoretical Physics
Abstract:
During the last few years, crowding effects on the physics of
proteins has become an increasingly popular topic of
research. This is is because most biological processes
involving proteins naturally take place in a crowded
environment, e.g. in the cellular environment where
macromolecules may occupy 30% of the volume. One such
biological process would be the formation of amyloid
aggregates, which are cross-beta-sheet rich protein structures
that have been associated with e.g. Alzheimer's disease. In
this work, we investigate the crowding effects on the
formation of amyloid fibrils by adding neutral crowding
particles (i.e. no explicit interaction except excluded volume
effects) to a lattice model of a solution of short
peptides. The peptides in the model interact via nearest
neighbour interactions which under certain conditions cause
formation of amyloid-like protein aggregates. We hypothesise
that the dominant effect of such crowding can be derived from
the effective increase in the peptide density, which depends
on the total volume occupied by the crowding particles
(`crowders'), and not on the total surface area of the
crowders, as have recently been discussed in the
literature. Any dominant surface effects, such as the recently
observed dual effect on the aggregation kinetics of amyloid
beta fibrils, is likely due to an explicit interaction between
the crowding particles and the peptides.
In addition, we develop an analytical approach that permits us
to study the thermodynamics of the model without crowders. In
this approach, we treat the collection of each type (i.e. of
given length and width) of aggregates in the system as a
collection of non-interacting objects in grand-canonical
ensembles, with the over-all constraint of peptide number
conservation. This method is used to study systems much larger
than those we can simulate using Monte Carlo methods, and to
compute an approximate phase diagram for the model.
LU TP 14-26